The compounds of the present invention are sodium channel blockers, in particular selective inhibitors of the voltage-gated sodium channel 1.7 (Nav1.7) which is involved in pain. Since other sodium channel subtypes are involved in different essential physiological processes such as heart activity (Nav1.5), muscle contraction (Nav1.4) and CNS neurotransmission (Nav1.1, 1.2 and 1.6), selectivity for Nav1.7 is believed to be associated with the potential elimination of side effects.
Several Nav1.7 blockers are described: The tarantula venom peptide Pro-TX-II is a potent inhibitor of Nav1.7 (Schmalhofer et al, Molecular Pharmacology 2008, 74, 1476-1484). A series of Benzazepinone Nav1.7 blockers are described to show activity in pre-clinical pharmacological models of pain (Williams et al, Biochemistry, 2007, 46(50), 14693-14703; McGowan et al., Anesth Analg, 2009, 109, 951-958). Amino-thiazoles and amino-pyridines are described as Nav1.7 inhibitors (WO2007109324) and isoxazoles are described as Nav1.7 inhibitors (WO2009010784).
Nonsense mutations in SCN9A, the gene coding Nav1.7, appear to be linked to Congenital Indifference to Pain (CIP) (Cox et al, Nature, 2006, 444(7121), 894-898). Patients with CIP are essentially completely indifferent to sensations that would cause pain in most individuals e.g. bone fractures, burns, dental abscesses, appendicitis and childbirth. Concurrently, they are able to distinguish between other sensations, such as thermal (hot/cold) and tactile (sharp/dull) stimuli (Goldberg et al, Clinical Genetics, 2007, 71(4), 311-319).
Recent clinical reports indicate that gain of function mutations in human Nav1.7 are typically associated with severe pathological conditions. Primary Erythermalgia has been associated with mutations T2573A and T2543C in Nav1.7 (Yang et al, Journal of Medical Genetics, 2004, 41(3), 171-4). Paroxysmal Extreme Pain Disorder is described in association with mutations M1627K, T14641 and I1461T located in the inactivation gate area of Nav1.7 (Fertleman et al, Neuron, 2006, 52(5), 767-774).
Thus selective inhibition of Nav1.7 channels may provide comprehensive analgesia.
Hence, there is a continuing need for compounds which may be useful for treating and preventing disorders or diseases which respond to inhibition of Nav1.7, particularly for compounds with improved efficacy, tolerability and/or selectivity.
Related, but structurally distinct triazines have been reported, e.g. as kinase inhibitors by Janssen (WO2004009562); as integrin inhibitors by Biochem Pharma (WO2000075129).